EP1327628B1 - Lipidisation de molecules hydrophiles - Google Patents

Lipidisation de molecules hydrophiles Download PDF

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Publication number
EP1327628B1
EP1327628B1 EP03006780A EP03006780A EP1327628B1 EP 1327628 B1 EP1327628 B1 EP 1327628B1 EP 03006780 A EP03006780 A EP 03006780A EP 03006780 A EP03006780 A EP 03006780A EP 1327628 B1 EP1327628 B1 EP 1327628B1
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Prior art keywords
bbi
lipid
cells
bbisspal
group
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Expired - Lifetime
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EP03006780A
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German (de)
English (en)
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EP1327628A2 (fr
EP1327628A3 (fr
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Wei-Chiang Shen
Hossein M. Ekrami
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University of Southern California USC
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University of Southern California USC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/56—Protease inhibitors from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/048—Pyridine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0065—Oxidoreductases (1.) acting on hydrogen peroxide as acceptor (1.11)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3515—Lipophilic moiety, e.g. cholesterol

Definitions

  • the present invention relates generally to the fields of biology and medicine. More particularly, the present invention relates to methods and compositions useful in increasing in mammals the absorption and retention of hydrophilic molecules, in particular peptides and proteins.
  • Alternative routes of protein and peptide delivery may include the buccal, nasal, oral, pulmonary, rectal and ocular routes. Without exception, these routes are less effective than the parenteral routes of administration. However, these routes of protein and peptide delivery are still far more attractive than the parenteral routes because they offer convenience and control to the patients. The oral route is particularly attractive because it is the most convenient and patient-compliant.
  • Mucosal barriers which separate the inside of the body from the outside (e.g. GI, ocular, pulmonary, rectal and nasal mucosa), comprise a layer of tightly joined cell monolayers which strictly regulates the transport of molecules. Individual cells in barriers are joined by tight junctions which regulate entry into the intercellular space. Hence, the mucosa is at the first level a physical barrier, transport through which depends on either the transcellular or the paracellular pathways [ Lee, V.H.L. (1988) CRC. Critical Rev. Ther. Drug Delivery Sys. 5, 69-97 ].
  • the cell membrane of mucosal barriers is a hydrophobic lipid bilayer which has no affinity for hydrophilic, charged macromolecules like proteins and peptides.
  • mucosal cells may secrete mucin which can act as a barrier to the transport of many macromolecules [ Edwards, P. (1978) British Med. Bull. 34, 55-56 ]. Therefore, unless specific transport mechanisms exist for protein and peptide, their inherent transport across mucosal barriers is almost negligible.
  • vesicles Once the carrier is bound to the cell surface, it is taken up into vesicles. These vesicles then become processed stepwise and can be routed to several pathways.
  • One pathway is the recycling of the vesicle back to the membrane from which it was invaginated.
  • Another pathway which is destructive to the conjugate, is the fusion with lysosomes.
  • An alternative pathway, and one which leads to the transcytosis of the conjugate, is the fusion of the vesicle with the membrane opposite to the side from which it was derived.
  • Also disclosed are methods for increasing the absorption or prolonging blood and tissue retention in a mammal of a sulfhydryl-containing compound of the general formula PSH are provided, in which a conjugate of general formula VI is formed from the sulfhydryl-containing compound and the conjugate is then administered to the mammal (for example, in an aqueous solution or an oral dosage unit).
  • Confluent cell monolayers 2 to 3 weeks old, and having a TEER value of approximately 500 ⁇ cm 2 , were first incubated with Dulbecco's MEM containing 1 % of FBS for 30 min at 37°C. Subsequently, the incubation medium was removed, and the 125 I-BBI (10 ⁇ g/ml) conjugates in 1.5 ml of the medium was added to the apical chamber of the transwells. To the basal chamber, 2.5 ml of the medium was added and the transwells were incubated at 37°C. At predetermined times, the entire basal chamber medium (2.5 ml) from each transwell was removed and counted for radioactivity using a gamma counter.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biomedical Technology (AREA)
  • Botany (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Manufacturing Of Micro-Capsules (AREA)

Claims (6)

  1. Utilisation d'un fragment contenant un lipide dans la fabrication d'un composé pour la délivrance d'un composé contenant un groupe sulfhydryle à des cellules de mammifère,
    dans laquelle ledit fragment contenant un lipide est un composé de formule générale V ;

            A-S-S-CH2-CR1(NHCOR2)C(=O)R3     V

    dans laquelle ledit composé pour la délivrance d'un composé contenant un groupe sulfhydryle a une formule générale VI ;

            P-S-S-CH2-C (COR3) R1NHC (=O) R2     VI

    dans laquelle A est un résidu d'activation aromatique ; P est un fragment issu du composé contenant un groupe sulfhydryle de formule générale PSH choisi dans le groupe constitué par des peptides, des protéines et des oligonucléotides ; R1 est hydrogène ou aryle ; R2 est un fragment contenant un lipide, comprenant un groupe lipidique ; et R3 est -OH, un fragment contenant un lipide, comprenant un groupe lipidique ou une chaîne d'acides aminés comprenant un ou deux acides aminés se terminant en -CO2H ou -COR2.
  2. Utilisation selon la revendication 1, dans laquelle A est 2-pyridyle ou 4-nitrophényle.
  3. Utilisation selon les revendications 1-2, dans laquelle R1 est hydrogène, R2 est un groupe lipidique et R3 est -OH.
  4. Utilisation selon les revendications 1-2, dans laquelle R1 est hydrogène, R2 est -CH2CH2CH(NH2)CO2H ou -CH2CH2CH (NHCO-lipide) CO-lipide et R3 est -NHCH2CO2H ou -NHCH2CO-lipide où au moins l'un de R2 et R3 comprend un groupe lipidique.
  5. Utilisation selon les revendications 1-2, dans laquelle ledit groupe lipidique est un substituant hydrophobe comprenant 4 à 26 atomes de carbone.
  6. Utilisation selon les revendications 1-2, dans laquelle ledit groupe lipidique est un substituant hydrophobe comprenant 5 à 19 atomes de carbone.
EP03006780A 1995-01-25 1996-01-25 Lipidisation de molecules hydrophiles Expired - Lifetime EP1327628B1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US349717 1989-05-09
US34971795A 1995-01-25 1995-01-25
US08/524,362 US5907030A (en) 1995-01-25 1995-09-05 Method and compositions for lipidization of hydrophilic molecules
US524362 1995-09-05
EP96903690A EP0820285B1 (fr) 1995-01-25 1996-01-25 Procedes et compositions de lipidisation de molecules hydrophiles

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP96903690A Division EP0820285B1 (fr) 1995-01-25 1996-01-25 Procedes et compositions de lipidisation de molecules hydrophiles
EP96903690.4 Division 1996-08-01

Publications (3)

Publication Number Publication Date
EP1327628A2 EP1327628A2 (fr) 2003-07-16
EP1327628A3 EP1327628A3 (fr) 2003-08-13
EP1327628B1 true EP1327628B1 (fr) 2007-08-29

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EP03006780A Expired - Lifetime EP1327628B1 (fr) 1995-01-25 1996-01-25 Lipidisation de molecules hydrophiles
EP96903690A Expired - Lifetime EP0820285B1 (fr) 1995-01-25 1996-01-25 Procedes et compositions de lipidisation de molecules hydrophiles

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EP96903690A Expired - Lifetime EP0820285B1 (fr) 1995-01-25 1996-01-25 Procedes et compositions de lipidisation de molecules hydrophiles

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US (4) US5907030A (fr)
EP (2) EP1327628B1 (fr)
JP (1) JP3814294B2 (fr)
KR (1) KR100438268B1 (fr)
CN (1) CN1139385C (fr)
AT (2) ATE371643T1 (fr)
AU (1) AU699827B2 (fr)
CA (1) CA2211442A1 (fr)
DE (2) DE69628290T2 (fr)
EA (1) EA000584B1 (fr)
ES (1) ES2200051T3 (fr)
FI (1) FI973048A (fr)
NO (1) NO973403L (fr)
WO (1) WO1996022773A1 (fr)

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WO1996022773A1 (fr) 1996-08-01
CN1175902A (zh) 1998-03-11
EA000584B1 (ru) 1999-12-29
FI973048A (fi) 1997-09-16
DE69637229D1 (de) 2007-10-11
CN1139385C (zh) 2004-02-25
EA199700143A1 (ru) 1997-12-30
AU4769296A (en) 1996-08-14
EP0820285B1 (fr) 2003-05-21
KR19980701667A (ko) 1998-06-25
JPH11500108A (ja) 1999-01-06
FI973048A0 (fi) 1997-07-18
EP0820285A4 (fr) 1998-04-22
JP3814294B2 (ja) 2006-08-23
NO973403L (no) 1997-09-17
NO973403D0 (no) 1997-07-23
US7052704B2 (en) 2006-05-30
KR100438268B1 (ko) 2004-09-04
ATE240729T1 (de) 2003-06-15
EP1327628A2 (fr) 2003-07-16
US20040054132A1 (en) 2004-03-18
EP0820285A1 (fr) 1998-01-28
US6225445B1 (en) 2001-05-01
DE69637229T2 (de) 2008-05-15
US5936092A (en) 1999-08-10
AU699827B2 (en) 1998-12-17
US5907030A (en) 1999-05-25
EP1327628A3 (fr) 2003-08-13
ATE371643T1 (de) 2007-09-15
DE69628290T2 (de) 2004-03-18
ES2200051T3 (es) 2004-03-01
DE69628290D1 (de) 2003-06-26
CA2211442A1 (fr) 1996-08-01

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